Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, and is expected to become more prevalent in the US over the next decade due to the dramatic rise in the incidence of hepatitis C virus infection. The most effective way to treat most cancerous tumors is by surgically removing them. Unfortunately, many subjects with hepatocellular carcinoma aren't candidates for surgery due to the size or location of the tumor, the existence of significant liver cirrhosis, or because the tumor has grown into the blood vessels. It would therefore be very useful to obtain a drug that would be effective against HCC.
A major challenge in the systemic treatment of HCC is cellular resistance to conventional cytotoxic agents, which may be attributed to the heterogeneity of genetic abnormalities acquired during the course of hepatocarcinogenesis. Traditional systemic chemotherapy of hepatocellular carcinoma has thus demonstrated poor results. Cabrera et al., Aliment. Pharmacol. Ther. 31, 461-476 (2010). Targeting molecular defects that allow HCC cells to evade apoptosis signaling consequently represents a viable strategy to improve patient outcome. Accordingly, a number of therapeutic agents targeting aberrant cellular growth and survival signaling pathways have been investigated for the treatment of HCC. Thomas et al., J Clin Oncol, 23, 8093-8108 (2005) Recently, sorafenib, a multi-kinase inhibitor, was approved for the treatment of advanced HCC. Llovet et al., N Engl J. Med., 359, 378-390 (2008) This therapy, however, only works in a subset of patients and is not curative, which underlies the urgency for identifying new therapies.
FTY720 is a synthetic sphingosine immunosuppressant that was recently approved for the treatment of relapsing multiple sclerosis. Cohen et al., N Engl J. Med., 362, 402-415 (2010). Evidence indicates that the immunosuppressive effect of FTY720 is attributable to the ability of its phosphorylated metabolite (p-FTY720) to induce T lymphocyte homing by targeting sphingosine-1-phosphate (S1P) receptors. Takabe et al., Pharmacol Rev., 60, 181-195 (2008) Recent studies indicate that FTY720 induces apoptosis and inhibits angiogenesis and metastasis in HCC, suggesting its translational potential as a cancer therapeutic agent. Lee et al., Carcinogenesis, 25, 2397-2405 (2004); Hung et al., Cancer Res, 68, 1204-1212 (2008). However, in addition to side effects common to immunomodulatory therapy, FTY720 was reported to cause cardiovascular complications, macular oedema, and brain inflammation, which may be due to FTY720 interacting with more than one S1P-receptor subtypes. Martin R., Nature, 464, 360-362 (2010). Accordingly, there remains a need for the development of more effective FTY720 derivatives.